[unreadable] This application seeks continuation of funding for years 14-19 for studies to elucidate the function and regulation of surfactant protein B in the developing and postnatal lung. This grant was initiated with the discovery of SP-B and its cDNA by this laboratory. The critical role of surfactant protein B in lung function and homeostasis was demonstrated through in vitro and in vivo studies. Newborn infants suffering from respiratory distress related to mutations or deficiency of SP-B were identified. Gene targeting and replacement studies in transgenic mice demonstrated the requirement of SP-B for lung function at birth, as well as in adult mice. Reduction of SP-B mRNA and protein to less than 50% resulted in severe abnormalities in respiratory physiology. However, the mechanisms and cellular responses involved in both regulation of SP-B and its function during injury, remain poorly understood. This application seeks to test the general hypothesis that factors regulating SP-B are critical to the maintenance of lung function in the perinatal and postnatal period, and that reduction or loss of SP-B results in stereotypic cellular and physiologic consequences involved in the pathogenesis of RDS and ARDS. We will identify 1) critical cis-acting elements and nuclear proteins mediating transcriptional control of the SP-B gene, 2) the role of TTF-1 phosphorylation and nuclear trafficking of TTF-1, via TAZ, 3) the precise temporal-spatial requirements of SP-B for postnatal respiratory function, and 4) the transcriptional responses of the lung to lethal and sublethal reductions in SP-B. We developed mice in which the human SP-B gene is conditionally replaced in the lung using a doxycycline regulatable lung specific element, completely rescuing the respiratory failure in SP-B gene targeted newborn and adult mice. With this model, temporal and spatial requirements for SP-B and its role in regulating alveolar homeostasis, including surfactant function, uptake, secretion, and tubular myelin formation will be discerned. Effects of severe reductions in SP-B on lung structure and function will be assessed. Transcriptional responses to decreased SP-B will be determined using RNA microarray, to identify the molecular pathways mediating or compensating for reduced SP-B/surfactant function in vivo. [unreadable] [unreadable]